Abnormal accumulation of amyloid beta protein (Aβ) and/or tau in the nervous system results in progressive damage to neurons leading to Alzheimer's Disease (AD) and fronto-temporal dementia (FTD). These devastating disorders affect over 5 million people in the US alone. Aβ is a 40 to 42 amino acid long peptide derived from the proteolysis of amyloid precursor protein (APP) by the gamma and beta-secretases. Accumulation of oligomeric forms of Aβ promotes degeneration by damaging the synaptic connections among neurons. In AD, accumulation of Aβ oligomers may be the result of alterations in the balance between the rate of Aβ synthesis, aggregation and clearance. Although most recent therapies for AD have been focused at blocking synthesis or aggregation of Aβ, relatively less has been done to promote clearance. The clearance of Aβ depends on removal by: i) chaperones (e.g., apoE, beta-2M, HSP's), ii) degrading enzymes (e.g., neprilysin (NEP), insulin-degrading enzyme (IDE), EDE), iii) non-lysosomal degradation (e.g., proteosome) and/or lysosomal degradation (e.g., by autophagy).
The use of polypeptides that can increase the clearance of Aβ aggregates via degradation (e.g., NEP, IDE), autophagy (e.g., Beclin), lysosomal enzymes (e.g., cathepsin) or binding molecules (e.g., apolipoprotein E (apoE), antibodies, beta-2M) has been described. The main problem in all of these cases is that the polypeptides of interest cannot enter into the CNS, or when they do they can only enter at very low levels—below their therapeutic value.